We will study the relationship between protein states involved in folding/collapse and with those involved in recognition especially concerning with DNA. The mechanisms governing molecular recognition by proteins and the transition of proteins from their unfolded state to their native state are fundamental biophysical questions that remain unanswered. We will relate the chemical potentials of peptide subdomains in various contexts to changes in solubility and conformation and thus ultimately to recognition and binding. Several proposed systems will be computationally tested in various multicomponent aqueous solutions. Our recent theoretical work suggests the solvent effect on the initial collapse toward folding and the early processes of molecular recognition have many common features. We will study the relation of solubility as a function of length and composition with respect to the available conformational manifold. We will use glycine oligomers as our model for the protein subdomain of UBX and the hinge-helix sequence of LacI. High precision free energy simulations and advances in approximate theory make the calculations of 2, 3 and even 4 component solutions feasible for these studies. We will calculate the chemical potential of these and other peptides and small proteins as well as the other solution components as a function of conformation and solution composition. Misfolded and unstructured domains represent important examples of disease states where the understanding of the recognition, self-recognition or folding process has important potential therapeutic implications. This is not a sequence to structure proposal. Rather we study the fundamental free energy surface of features common to all proteins and the relation to binding. PUBLIC HEALTH RELEVANCE: The mechanisms governing protein-DNA recognition and the transition of proteins from their unfolded state to their native state are unanswered fundamental biophysical questions. Refolding often occurs in DNA binding. Misfolded and unstructured domains represent important examples of disease states where the understanding of the recognition, or folding process has important potential therapeutic implications.